Peroxisome proliferator-activated receptor α or PPARα belongs to a class of nuclear hormone receptors1 that participates in a diverse range of biological functions including control of fatty acid transport and catabolism2, anti-inflammation3, immuno-modulation4, and anti-oxidation5. However, in a recent study6, it has been shown that PPARα also plays an important role in the modulation of synaptic function in hippocampus via transcriptional upregulation of CREB. It has also been delineated that activation of PPARα in hippocampal neurons leads to the increase in ADAM10 transcription and subsequent non-amyloidogenic proteolysis of APP21. These reports highlight a lipid-independent role of PPARα in controlling brain function. Otherwise, it was believed that the presence of peroxisomes in abundance could be important for the compensation of mitochondrial instability in the adult brain hippocampus7.
Like many other nuclear hormone receptors, it is not known if all the biological activity of PPAR-α also depends on its binding with the ligand and subsequent translocation to the nucleus. Since interaction with ligand plays an instrumental role in modulating the biological effect of most nuclear hormone receptors22, an investigation into the existence of endogenous ligands of PPARα in the hippocampus was prompted. Successful identification of endogenous modulators of PPARα would aid in understanding the endogenous regulation hippocampal function and memory by PPARα. However, little is known about the presence of endogenous ligands of PPARα in the hippocampus and their role in regulating the synaptic activity. Although endocannabinoid-like molecules including oleoylethanolamide23,24 and palmitoylethanolamide25, the fatty acid derivative 20-carboxy-arachidonic acid26, and leukotriene B427 have been considered as endogenous PPARα ligands, these compounds are ubiquitously present in different tissues including liver28, kidney29 and brain30. Furthermore, these compounds display a wide range of biological activities starting form antioxidant, anti-inflammation to neuroprotection25,29. In attempt to find an endogenous ligand of PPAR-α, a recent study8 identifies that 1-palmitoyl-2-oleoyl-sn-glycerol-3-phosphocholine (16:0/18:1-GPC) could serve as a potent ligand of PPAR-α in liver. However, until now, nothing is known about the presence of endogenous ligand(s) in the hippocampus that are capable of modulating the PPARα activity in hippocampal neurons.
In order to identify physiologically available ligands, affinity purification was performed followed by gas phase mass spectrometry (GCMS) analyses in the nuclear extracts of lenti*ppara-overexpressed neurons. Then, the existence of these molecules was confirmed by affinity purification of hippocampal extracts collected from wild-type and Ppara-null animals against GST-PPAR-α recombinant protein followed by GCMS analyses. These analyses identified three unique ligands 3-hydroxy-(2,2)-dimethyl butyrate (HMB), hexadecanamide (HEX), and 9-Octadecenamide (OCT) in brain hippocampus. Further structural analyses revealed that two key amino acid residues Tyrosine 314 and 464 in the ligand binding pocket of PPARα are important for the binding with these ligands, which was confirmed by making site-directed mutated constructs of PPARα, subsequent expression of these constructs in neuronal cells using lentiviral strategy, and GCMS analyses of the affinity-purified nuclear fraction. The role of these ligands in controlling the expression of synaptic proteins and regulating the synaptic function of hippocampal neurons has also been analyzed.
The HMB, HEX and OCT ligands induce the activation of PPARα in brain cells and increase synaptic functions via upregulation of different synaptic molecules and calcium entry. What is needed in the art are PPARα ligands for modulating PPARα activity and for treatment of disorders such as dementia, neurological disorders, lysosomal storage disorders and body weight disorders.